LGN Activity Patterns during Ocular Dominance Plasticity in vivo By Monica L. Linden S.B. Mathematics with Computer Science, S.B. Brain and Cognitive Sciences Massachusetts Institute of Technology, 2002 SUBMITTED TO THE DEPARTMENT OF BRAIN AND COGNITIVE SCIENCES IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN NEUROSCIENCE AT THE MASSACHUSETTS INSTITUTE OF TECHNOLOGY JUNE 2008 © Massachusetts Institute of Technology All rights reserved Signature of Author: ____________________________________________________________ Department of Brain and Cognitive Sciences May 13, 2008 Certified by: ___________________________________________________________________ Mark F. Bear, Ph.D. Picower Professor of Neuroscience Thesis Supervisor Accepted by: __________________________________________________________________ Matthew A. Wilson, Ph.D. Professor of Neurobiology Chairman, Committee for Graduate Students LGN Activity Patterns during Ocular Dominance Plasticity in vivo By Monica L. Linden Submitted to the Department of Brain and Cognitive Sciences on May 13, 2008 in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Neuroscience ABSTRACT Perturbations of sensory experience in young animals are known to cause lasting changes in adult brain function. For example, monocular visual deprivation by lid closure (MC) leads to a loss of cortical responsiveness of the deprived eye and a concomitant visual impairment. This ocular dominance (OD) plasticity is a well-studied model of experience-dependent cortical plasticity. While much is known about the anatomical, physiological and biochemical changes that occur in primary visual cortex following OD plasticity, the input patterns that lead to these changes have not been characterized. Visual input travels from the retina through the dorsal lateral geniculate nucleus (dLGN) of the thalamus and then into visual cortex. Several models of the thalamic activity patterns which drive OD plasticity have been proposed, but the assumptions about the pattern and amount of input activity from thalamus to cortex during deprivation have not been experimentally validated. Therefore, we performed extracellular recordings from the dLGN of animals during periods of visual manipulation. Contrary to previous hypotheses, the present findings demonstrate that MC does not alter the overall firing rate of neural activity in the dLGN. Instead, MC alters the pattern of neural spike trains such that there is a decrease in simultaneous firing of neighboring neurons. Moreover, the elimination of visual input from the retina, a form of deprivation which does not lead to deprived-eye depression, leads to a dramatic increase in thalamic bursting. Additionally, there are subtle qualitative differences between dLGN activity in juveniles and adults during MC, and this may contribute to differences in OD plasticity with age. These findings substantially alter the interpretation of previous studies and define the activity patterns that govern cortical plasticity in vivo. Furthermore, this work may have important implications for treatments of developmental disorders including ambylopia. Thesis Supervisor: Mark F. Bear, Ph.D. Title: Picower Professor of Neuroscience Monica L. Linden [email protected] Education: Massachusetts Institute of Technology Doctor of Philosophy – June, 2008 Cambridge, MA Ph.D. in Neuroscience, Department of Brain and Cognitive Sciences. Major: Systems Neuroscience, Minor: Computational Neuroscience. Massachusetts Institute of Technology Bachelor of Science – June, 2002 Cambridge, MA Bachelor of Science degrees in Mathematics with Computer Science and Brain and Cognitive Sciences, Minor: Ancient and Medieval Studies. Awards/ Honors: NIH National Research Service Award Predoctoral Fellowship (2007) Walle Nauta Award for Continuing Dedication to Teaching (2006) Dean’s Educational and Student Advising Award (2005) Agnus MacDonald Award for Excellence in Undergraduate Teaching (2005) National Science Foundation Graduate Research Fellowship (2002) MIT Brain and Cognitive Sciences Award for Academic Excellence (2002) Phi Beta Kappa Honor Society Sigma Xi Research Honor Society Teaching Experience: MIT 9.01: Introduction to Neuroscience – Head TA Fall 2004, Fall 2005 Taught one weekly section (~25 students) under Profs. Mark Bear and Sebastian Seung. Coordinated TAs, multiple guest lecturers, and the writing staff. MIT 9.00: Introduction to Psychology – TA Fall 2003 Taught two recitation sections (~25 students) under Prof. Jeremy Wolfe. MIT Orientation for Graduate Teaching Staff – Workshop Facilitator Fall 2005 Co-facilitated “Problems, Pitfalls, Booby Traps and Surprises (in Teaching)” workshop during the fall TA orientation, sponsored by the Teaching and Learning Lab. Research Experience: MIT Picower Center for Learning and Memory – Bear Lab Cambridge, MA June, 2003 – 2008 Graduate Student Researcher: Performing in vivo electrophysiology in awake rodents to understand various aspects of neural plasticity in the visual system. National Security Agency – Students' Summer Program Government Communications Headquarters Cheltenham, UK Summer, 2002 Intern: One of two student liaisons selected to represent the US at this British security agency. Developed mathematical models to analyze systems. Prepared a research report for internal publication and presented results to internal mathematics community. MIT Picower Center for Learning and Memory – Tonegawa Lab Cambridge, MA September, 2001 – March, 2002 Undergraduate Researcher: Data analysis for electrophysiological studies in genetically manipulated mice. National Security Agency – Director's Summer Program Ft. Meade, MD Summer, 2001 Intern: Developed mathematical models to analyze and evaluate data. Prepared a research report for internal publication and briefed the Director of the Agency. Top Secret Clearance. Consulting: Lippincott Williams and Wilkin – Subject Matter Expert Fall 2005 Reviewed manuscripts of ancillary material, specifically “Student Assignments and Activities” for Neuroscience, Exploring the Brain, 3rd Edition by Bear, Connors and Paradiso. This is the textbook used in 9.01 – Introduction to Neuroscience, co-authored by Prof. Bear. Publications & Presentations: M.L. Linden, A.J. Heynen, R. Haslinger, M.F. Bear. (2008) Thalamic activity that drives visual cortical plasticity. Submitted M.L. Linden, A.J. Heynen, R. Haslinger, E.N. Brown, M.F. Bear. LGN activity patterns during ocular dominance plasticity. Picower-RIKEN Symposium, November 8 – 9, 2007. Massachusetts Institute of Technology, Cambridge, MA. Poster Presentation. M.L. Linden, A.J. Heynen, R. Haslinger, E. N. Brown, M. F. Bear. LGN activity patterns during ocular dominance plasticity. Society for Neuroscience, Abstracts, November 3 – 7, 2007. Society for Neuroscience Annual Meeting, San Diego, CA. Poster Presentation. M.L. Linden. LGN activity patterns during ocular dominance plasticity. MIT Brain Lunch Seminar Series, October 15, 2007. Massachusetts Institute of Technology, Cambridge, MA. Lecture. M.L. Linden. LGN activity patterns during ocular dominance plasticity. Picower Institute for Learning and Memory, Annual Retreat, May 30 – June 1, 2007. Cape Cod, MA. Lecture. M.G. Shuler, M.L.Linden, M.Bear. (2004) Learning induced, persistent reward-related activity in the primary visual cortex of adult rodents. Society for Neuroscience, Abstracts, October 23 – 27, 2004. Society for Neuroscience Annual Meeting, San Diego, CA. Acknowledgments “We were but stones, your light made us stars” –Low Light, Pearl Jam There are numerous people whom I’d like to thank, without which my thesis project would not have been as successful. First of all, I’d like to thank Mark Bear. I thoroughly enjoyed working on the fundamental problem which he gave to me, and I was constantly driven to work through my frustrations because I knew there had to be answers. I appreciate all his support throughout the project, even after I upended his hypotheses. I would also like to thank the rest of my thesis committee for their helpful insights: Mriganka Sur, Matthew Wilson and especially Harvey Swadlow, who responded patiently to my emails even when I sent several in the same day. I’d also like to acknowledge my funding sources including a graduate research fellowship from NSF and an NRSA predoctoral fellowship from NINDS/NIH. The Bear Lab provided an incredibly supportive environment throughout my graduate career. Arnie Heynen was a constant source of scientific expertise and emotional support. I couldn’t have done this without him. Marshall Shuler patiently taught me how to be an electrophysiologist and was always there to help me think through my ideas and to challenge my assumptions. Jason Coleman was always willing to help me and provided invaluable knowledge of the dLGN. Sharing lab space with Jonathan Whitlock meant my day in lab would be much more fun. Suzanne Meagher always took care of me, and Erik Sklar fixed everything I managed to break. Our technicians, Caroline Dudley, Cindy Poo, Tina Udaka, and especially Kathleen Oram who did my histology, were wonderful. Gordon Smith always had great answers to questions I asked him, even when they had nothing to do with what he was studying, and even when I asked him quietly during lab meeting. Misha Frenkel, Gül Dölen, Sam Cooke and Emily Osterweil were great sounding-boards for discussing my problems. Lena Khibnik, Rahmat Muhammad, and Wendy Chen were all wonderful friends inside and outside the lab,